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A nasal mucoadhesive thermo reversible in-situ gel appears very attractive since it is fluid-like prior to nasal administration and can thus easily be installed as a drop allowing accurate drug dosing. The feasibility of developing an efficacious intranasal formulation of the potent antiemetic drug Ondansetron HCL has been undertaken in this work. The ultimate goal is to circumvent the first-pass elimination of the drug when taken orally. Poloxamers P407 and P188 (20/5% w/v) were used using cold method to prepare thermo reversible gels as they have excellent thermo-sensitive gelling properties, water solubility , good drug release, low toxicity and irritation. Mucoadhesive polymers like chitosan high molecular weight (HMW), sodium carboxymethyl cellulose low molecular weight (LMW) and polyvinylpyrrolidone K30 (PVP) were used at concentration of 0.5 % (w/v) to form thermo reversible gels. Three nasal in-situ gels with desirable Tsol-gel in the range of 30-35oC were developed. pH, mucoadhesion, rheological measurements, in vitro release and ex-vivo permeation studies were performed to evaluate the prepared gels. The incorporation of chitosan to poloxamer polymers showed significant increase in the mucoadhesion ability. The prepared gels exhibited non-Newtonian shear thinning behavior at 35oC. Drug contents were in the range of 97.8-100.1%. The release pattern was enhanced by the PVP polymer, in opposition; chitosan and NaCMC retarded it. Concerning permeation through sheep nasal mucosa, the steady state flux (Jss) of the three formulae was found to be 3.57, 5.64 and 3.81 μg/cm 2 .min., respectively. No marked alteration in the histological structure of the nose epithelial cell membrane of male Wister rats after application of the formed gels was observed to confirm their safety. The bioavailability for the optimized formulation was 86.98% providing that intranasal route could be promising for Ondansetron HCL delivery. INTRODUCTION Nasal delivery is increasingly considered to be an alternative route for drugs that currently require parentral administration. As a site for systemic absorption the nasal route provide means of avoiding first pass metabolism (Ultarwar et al., 2012). The development of in situ gel systems has received considerable attention over the past few years. These systems possess potential advantages like simple manufacturing process, reduced frequency, ease of administration, improved patient compliance and comfort (Miyazaki et al 2003). In-situ gel forming drug delivery is a type of mucoadhesive drug delivery system. In contrast to very strong gels, they can be easily applied in liquid form to the site of drug absorption, swell to form a strong gel capable of prolonging the residence time of the active substance. Both natural and Az. J. Pharm Sci. Vol. 50, September, 2014 192 synthetic polymers can be used for the production of in-situ gels. In-situ gel formation occurs due to one or combination of different stimuli like pH change, temperature modulation and ionic crosslinking (Kant et al., 2011). Poloxamers or pluronics are the series of commercially available copolymers of non-ionic nature. They were used as an in situ gel forming polymer together with mucoadhesive polymers like NaCMC, chitosan and PVP to ensure long residence time at the application site (Alexandridis and Hatton, 1995). Ondansetron hydrochloride (ON) has been used to prevent and control both nausea and vomiting after cancer chemotherapy, radiotherapy and surgery. Unlike metoclopramide, (ON) is known not to induce the undesirable side effect such as extrapyramidal reactions. It should be administered 30 min before chemotherapy, and it tends to be discharged by vomiting (Rolia and Del Favero, 1995). It has been used by oral and injectable administration. It is rapidly absorbed orally, but extensively metabolized by the liver (Figg et al., 1996). Based on this, the feasibility of developing an effective intranasal formulation of the potent antiemetic drug (ON) has been undertaken in this study. The aim of this study was to formulate (ON) in a mucoadhesive in-situ gelling system to increase the residence time of the drug in the nasal cavity. The system would allow accurate drug dosing. The poloxamer 407/188 gel was used as the base whereby its gelation temperature was modulated so as to be liquid at 25°C and gels at 32°C. Additionally, different mucoadhesive polymers were used together with poloxamer to fortify the adhesion of the in-situ gel to the nasal mucosal surface. MATERIALS AND METHODS Materials Ondansetron hydrochloride dihydrate (ON) was kindly supplied from (Ameriah pharmaceutical company, Cairo, Egypt). Risperidone (pharo, Egypt), Zofran 8mg tablets, Danset ampoules 4mgm/2ml (glakso, Egypt), Chitosan (Cs) high Mol.Wt, Mucin from porcine stomach, Poloxamer 407 and 188 (Sigma–Aldrich Company, St. Louis USA). Haematoxylin–eosin (Bark Scientific Limited, UK), thiopental (Epico, Egypt), 0.9% saline solution (Haydelina, Egypt), sodium carboxy methyl cellulose (NaCMC), poly vinyl pyrrolidone K30 (PVP), sodium hydroxide, sodium chloride, potassium chloride, calcium chloride dihydrate, propylene glycol (Fluka Chemika-BioChemika, Switzerland), benzalkonium chloride, iso-propyl alcohol, formalin, acetonitrile, zinc sulphat, ammonium acetate, glacial acetic acid, acetonitrile were purchased from (Sigma-Aldrich Chemicals St. Louis, MO, USA). Freshly prepared phosphate buffer saline solution pH 6.4. All other chemicals were of reagent grade and were purchased from (EL-Nasr Company Cairo, Egypt). Equipment Electric balance (Sartorius GMBH, Germany), Brookfield DV-III ultra programmable cone and plate rheometer fitted with a spindle number 52 and controlled with rheometer operating software (Brookfield, USA), dissolution tester apparatus II (Hanson research test, USA), UV 240 double beam spectrophotometer (Schimadzu Corporation, Kyoto, Japan), pH meter (Genway ltd, UK), Ultra Centrifuge (Jouan, France), magnetic stirrer (Jenway, UK), Fridge (Toshiba, Egypt), light microscope (Euromex, The Netherlands), HPLC equipped with G1311A quaternary pump and UV detector (VWD-G1314A, agilent, Germany). Thermostatic water bath (Poly Science, USA), diffusion cell (designed as per the dimensions given by (Pisal et Az. J. Pharm Sci. Vol. 50, September, 2014 193 al), ultrasonic sonicator (Crest Trenton, U.S.A), vortex (snijders, Holland), 0.45μm membrane filter (nupore, India). Preparation of (ON) thermoreversible gels The formulations were prepared on the weight ratio according to cold method (Pisal et al., 2004). Medicated in-situ gelling formulations composed of 20/5% w/v P407/P188 were prepared with the addition of mucoadhesive polymers namely: NaCMC (LMW), Chitosan (HMW) and PVP K30. The drug, benzalkonium chloride and the polymers were stirred in the calculated amount of distilled water with proper amount of propylene glycol (10% v/v) at room temperature. The dispersions were cooled; the poloxamers were added slowly and then left to hydrate at 4°C. (chitosan was dissolved in 0.1N Acetic Acid). Table (1) illustrates composition ratio of in-situ gel components. Visual appearance, clarity and pH of in-situ gel The clarity and color of the formulated solutions determined by visual inspection under black and white background (Mahadlek 2008). The pH of the medicated formulations was determined by bringing the electrode of the pH meter in contact with the surface of the formulation and allowing it to equilibrate for 1 min. The experiments were run in triplicates. Gelation temperature determination The gelation temperatures of formulations were determined using a modified “Visual Tube Inversion Method” (Ur-Rehman et al., 2011). Approximately 4 g of thermo-sensitive gel was transferred to vials and incubated in a thermostatic water bath with an increasing rate of 1oC/min; an equilibration period of 5 min was applied after each temperature raise. Observation of the gel surfaces was taken at every temperature point by tiling the vials to the horizontal position, the temperatures at which the surfaces remained immobile within 30 sec were measured by an inserted thermometer and were recognized as the gelation temperatures. The measurements were performed in triplicate. Measurement of steady shear viscosity The rheological properties of the in-situ gelling formulations were studied using (cone and plate Brookfield viscometer) (Zaki et al., 2007). The measurements were made at 35±0.1°C using spindle 52 at a shear rate ranging from 0.5 to 100 rpm. The shear rate (γ) in S -1 and the viscosity (η) in cps were determined and fitted to the power law constitutive equation: η = m γ n-1 (Tung and Fang, 1994) where m is the consistency index and n is the flow index. If n=1, this indicates Newtonian behavior while n<1 indicates shear thinning flow and the lower the value of n the more the thinning the formulation (Asasutjarit et al., 2011). Mucoadhesion measurement The mucoadhesive behavior was evaluated according to the method described by (Hassan and Gallo, 1990) based on the idea that the chemical interaction and entanglements between the polymer and glycoproteins in mucus causes a rheological synergism. Dried mucin was hydrated with simulated nasal electrolyte fluid (SNEF) by stirring for 3 hrs at room temperature. Six grams of mucin dispersion were mixed for 15 min with 2 gm of each polymer solutions before measurement. The viscosity of mucin (15% w/w) was measured in absence and presence of polymer solution to evaluate the mucoadhesion properties of the tested polymer solution. The Az. J. Pharm Sci. Vol. 50, September, 2014 194 measurement was done at 35±1 o C and shear rates (D) of 10, 20, 50 and 100 s −1 . All measurements were performed in triplicate. The viscosity of mucoadhesion component (ηb) was calculated from the following equation: ηb = ηt − ηm − ηp. Where ηt is viscosity of mucin with polymer, ηm is viscosity of mucin without polymer and ηp is visco

PREPARATION AND CHARACTERIZATION OF THERMOSENSITIVE MUCOADHESIVE IN_SITU GELS FOR NASAL DELIVERY OF ONDANSETRON HYDROCHLORIDE